Apoptosis resistance in cancer – what’s the “lnc” to noncoding RNA?

October 30, 2016

“All that lives must die,” Shakespeare writes in Hamlet, and this principle is largely true. Unfortunately, when it comes to cancer cells, the normal rules of cell growth and death don’t apply – cells multiply indefinitely, resist growth inhibition signals and escape programmed cell death. To defeat cancers, we need to reveal and address the multiple mechanisms they use to evade apoptosis.

Cancer cells avoid death in a variety of ways, and several of these mechanisms involve long noncoding RNAs (lncRNA). An increase in available tools for studying lncRNA, including lncRNA-specific qPCR arrays and RNA sequencing, makes the secrets of their roles in biological pathways more accessible than ever before.

A new review published in Cell Death & Disease (1) gives a comprehensive overview of what’s currently known about noncoding RNAs, including lncRNA and microRNA, in the regulation of cell death. Some of the pro- and anti-apoptotic mechanisms used by the reviewed lncRNAs include:

– Boosting BAX inhibition via AKT by upregulating Wnt6 (UCA1)

– Inhibiting caspase cleavage (HOXA-AS2, AFAP-AS1)

– p53 regulation (positive by MEG3 and Wrap53alpha, negative by ROR)

– Regulation of intrinsic apoptosis (MEG3, PTENpg1, INXS, lncRNA-LET)

– Regulation of extrinsic apoptosis (sFas, FAS-AS1, MALAT1)

Prostate cancer was one of the first diseases to be linked to a specific lncRNA biomarker, PCA3, and many other lncRNAs have been associated with prostate cancer as well, including HOTAIR and PCAT-1. Download our application note on identifying lncRNA biomarkers for prostate cancer. A new study published in the Journal of Biological Chemistry explores how the lncRNA SOCS2-AS1 blocks apoptosis in prostate cancer cells (2). SOCS2-AS1 is the antisense transcript of the SOCS2 gene, which causes cytokine feedback inhibition via dephosphorylation of JAK or STAT. Read more about SOCS2

To identify lncRNAs induced by androgen in prostate cancer cells, the authors first used RNA sequencing of two prostate cancer cell lines and their corresponding castration-resistant lines. Isolating RNA using RNeasy and performing qRT-PCR, they further examined 5 lncRNAs and found that SOCS2-AS1 levels were higher in the castration-resistant lines. This finding was present in RNA-seq analysis as well. They identified androgen receptor binding sites at a promoter used by both SOCS2 and SOCS2-AS1, and found that AR bound to this promoter even in the absence of dihydrotestosterone, and more so at low levels of the hormone. Next, they showed that lncRNA drives growth of both hormone-dependent and castration-resistant prostate cancer cells, as well as cell migration, by using siRNA knockdown and overexpression experiments.

To explore the effects of SOCS2-AS1 on apoptosis, the team profiled gene expression after knockdown of both SOCS2-AS1 and SOCS2. Nearly 600 apoptosis-related genes were upregulated following SOCS2-AS1 knockdown. In particular, in castration-resistant cells, knockdown led to upregulation of TNFSF10, TRAIL receptor 1, and Fas. To confirm the effects implied by the gene expression results, the team knocked down SOCS2-AS1 and SOCS2 in hormone-dependent and castration-resistant cells and performed a cell proliferation assay and TUNEL assay. They found that cell viability under docetaxel treatment was diminished and apoptosis was increased in both cell types after SOCS2-AS1 knockdown, and the opposite effects were observed with SOCS2-AS1 overexpression, indicating that SOCS2-AS1 leads to resistance of apoptosis in prostate cancer cells.

What does the regulation of apoptosis by the SOCS2-AS1 lncRNA mean for prostate cancer research and our understanding of lncRNA? Castration-resistant prostate cancer remains difficult to treat, and the discovery that this lncRNA may be involved in its progression via its effects on apoptosis yields a new target for research into potential therapies. This study is also another step on the path toward revealing the full picture of how lncRNAs govern gene expression in cell death and cancer, a path that is ever-evolving and will no doubt continue to be unveiled in the coming years.

Ali Bierly, PhD is a Global Market Manager in Translational Sciences at QIAGEN, and has written on a number of scientific topics in the biotech industry as the author of QIAGEN's Reviews Online. She received her PhD from Cornell University in 2009, studying the immune response to a protozoan parasite, Toxoplasma gondii. Ali has a keen interest in the emerging importance of microRNA and other circulating nucleic acids as biomarkers for disease.

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